9RJC

Apo Structure of the Human Signal Peptidase

This is a non-PDB format compatible entry.

Summary for 9RJC

• Entry DOI: 10.2210/pdb9rjc/pdb
• EMDB information: 54011
• Descriptor: Signal peptidase complex catalytic subunit SEC11A, Signal peptidase complex subunit 1, Signal peptidase complex subunit 2, ... (4 entities in total)
• Functional Keywords: signal peptidase complex, protein biogenesis, secretory pathway, membrane thinning, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 67731.79

Authors

Liaci, A.M.,Vismpas, D.,Skalidis, I.,Koh, F.A.,Abhay, K.,Forster, G.F. (deposition date: 2025-06-12, release date: 2026-05-27, Last modification date: 2026-06-03)

Primary citation

Manuel Liaci, A.,Vismpas, D.,Kjolbye, L.R.,Skalidis, I.,Pereira, G.P.,Koh, A.F.,Grollers-Mulderij, M.,Kotecha, A.,Souza, P.C.T.,Forster, F.
Structural basis of signal peptide recognition by the signal peptidase complex.
Nat Commun, 2026

PubMed Abstract: The signal peptidase complex (SPC) is responsible for cleaving signal peptides (SPs) from approximately 10% of the human proteome. SPs are characterized by a tripartite structure, consisting of an N-terminal n-region, a central helical h-region and a C-terminal c-region, each defined by rather general chemical properties rather than strict sequence conservation. Despite their sequence diversity, SPC recognizes and processes SPs with exquisite specificity. Here, we present a 2.6 Å cryo-EM map of the human SPC-A, one of two SPC paralogs, bound to a model SP. The c-region binds to a hydrophobic binding groove near the active site, a narrow gate marks the transition from c- to h-region, and the h-region localizes in a transmembrane (TM) window. Substrate engagement stabilizes N- and C-terminal helices of Sec11A, which frame the SP and are unresolved in the apo structure. Molecular dynamics (MD) simulations confirm a stable hydrogen-bonding network at the c-region and indicate dynamic interactions within a thinned lipid environment at the TM window. AlphaFold modeling supports this binding mode across physiological SPs. Collectively, our structural and computational analyses explain how the SPC achieves its specificity by combining the selectivity of the luminal binding groove and of the transmembrane window.

PubMed: 42173868
DOI: 10.1038/s41467-026-73423-3

Experimental method

ELECTRON MICROSCOPY (4.2 Å)